Hair growth involves division of hair matrix cells at the hair root and formation of hair by cells thus produced. Hair grows in a cycle referred to as the hair cycle, which repeats the anagen, catagen, and telogen phases. Follicle dermal papilla cells control the hair cycle by exerting an influence upon the proliferation and differentiation of hair follicle epithelial stem cells, through the production and release of growth factors. The activation of follicle dermal papilla cells and hair matrix cells is said to contribute to the hair-growth mechanism.
At hair follicles, blood vessels are actively remodeled depending on the hair cycle, and any disturbances in angiogenesis then lead to an insufficient supply of nutrients and oxygen for hair formation. A deficiency in blood flow from the hair follicle vascular network is said to involve the pathology of male pattern baldness (AGA).
The following facts are known concerning the genes of follicle dermal papilla cells in connection with hair development and hair growth. FGF-7 and IGF-1 are among known growth factors that are secreted by follicle dermal papilla cells into hair matrix cells. These genes serve to maintain the hair follicle growth. Vascular endothelial growth factor (VEGF), which is secreted by follicle dermal papilla cells, is involved in the formation of hair follicle blood vessels, and has the effect of proliferating follicle dermal papilla cells in an autocrine manner. The expression level of VEGF, however, decreases as the hair cycle transitions from the anagen phase to the catagen phase. The expression of the VEGF gene is reduced in the hair tissue of individuals with AGA (male pattern baldness). VEGFB competitively binds to VEGFR-1, which is a receptor on which VEGF acts. While VEGFB proliferates vascular endothelial cells or has blood vessel permeability-enhancing activity, its effects upon hair follicles are uncertain.
The Wnt family is known to be involved in hair follicle development. Wnt5a of the Wnt family is expressed in follicle dermal papilla cells, as well as outer root sheath cells and inner root sheath cells, is involved in the development of hair follicles, and has the effect of preventing cell death of follicle dermal papilla cells. In follicle dermal papilla cells, the expression level of Wnt5a is known to become maximal during the anagen phase (Non Patent Literature 1: PLoS One 4, e5354 (2009); Non Patent Literature 2: Acta Histochemica 113, 608-612 (2011)).
Alkaline phosphatase (ALP, ALPL) serves as an index of the activity of follicle dermal papilla cells including hair growth-inducing ability.
Versican, which is a chondroitin sulfate proteoglycan, is known to increase in hair follicles during the anagen phase and decrease toward the telogen phase (Non Patent Literature 3: J. Dermatol. Sci. 39, 147-154 (2005)), and its expression level is correlated with hair growth-inducing activity.
Various drugs having hair-restoration effects are known. Of the drugs ranked in terms of potency on a scale of 1 to 5 in “Guidelines for the Treatment of Alopecia” by the Japanese Dermatological Association, minoxidil and finasteride (for men only) are classified into the category of “strongly recommended”, while adenosine is classified into the category of “the application may be considered, but lacks sufficient evidence”. The guidelines also mention carpronium chloride, t-flavanone, 6-benzylaminopurine (cytopurine), pentadecane, ketoconazole, and cepharanthine.
Minoxidil has been reported to activate the SUR (sulfonylurea receptor), and thereby suppress hair matrix cell apoptosis through mitochondrial ATP-sensitive K channel opening, and have the effect of improving the hair tissue blood flow through vascular smooth muscle ATP-sensitive K channel opening and promoting the production of cell growth factors such as VEGF from follicle dermal papilla cells.
Finasteride inhibits 5 α-reductase, which is an enzyme that converts testosterone into dihydrotestosterone, and is thus effective against AGA, which is male alopecia induced by dihydrotestosterone. Finasteride, however, is not effective against forms of alopecia other than AGA such as alopecia areata.
t-Flavanone is believed to suppress the expression of TGF-β that suppresses the proliferation of hair matrix cells, thereby promoting hair growth.
6-Benzylaminopurine suppresses the expression of the NT-4 gene involved in the apoptosis of hair matrix cells in follicle dermal papilla cells, thereby growing hair and reducing hair shedding.
Adenosine directly acts on the follicle dermal papilla, and serves to promote hair growth by increasing the amount of production of a hair growth-promoting factor, FGF-7, to prolong the anagen phase of the hair cycle, thereby growing strong thick hair instead of thin weak hair.
Additionally, the following components are disclosed as having hair-restoration effects: low-molecular-weight acidic mucopolysaccharides, i.e., hyaluronic acid, chondroitin sulfate, dermatan sulfate, and heparan sulfate, in JP H05-38726 B (Patent Literature 1); sulfated polysaccharides and/or salts thereof in JP H09-188607 A (Patent Literature 2); an alginate oligosaccharide or a salt thereof in JP H10-203930 A (Patent Literature 3); sialic acid and sialic acid derivatives in JP Patent No. 2555389 (Patent Literature 4); the sulfuric acid ester and phosphate ester of β-1,3-glucan as examples of β-1,3-glucan derivatives in JP 2004-238286 A (Patent Literature 5); fucoidan in JP Patent No. 3831252 (Patent Literature 6); and an acidic xylooligosaccharide in JP Patent No. 3719207 (Patent Literature 7). These components, however, are neither disclosed nor suggested to act on follicle dermal papilla cells. Hair-restoration effects have also been obtained with sodium salts of these components.
JP Patent No. 2583812 (Patent Literature 8) discloses that a hair-nourishment effect is enhanced by exchanging cations of at least one acidic polysaccharide selected from the group consisting of alginic acid, carrageenan, pectin, and dextran sulfate, with hydrogen ions.
JP Patent No. 3240102 (Patent Literature 9) discloses that a phosphorylated saccharide calcium salt solubilizes calcium, and thus, is used for oral compositions or fertilizer. JP 2006-249077 A (Patent Literature 10) discloses the use of a phosphorylated saccharide calcium salt for external preparations for skin, and discloses its effects of improving the supply of minerals, promotion of collagen production in the epidermis, and water-retention effect of the skin. WO 2007/040027 (Patent Literature 11) discloses that a combination of a phosphorylated saccharide calcium salt and ascorbic acid or the like markedly improves the moisturizing effect or anti-aging, the cell-activation effect, or the whitening effect of the skin. JP 2012-77044 A (Patent Literature 12) discloses that a phosphorylated saccharide calcium salt has the effect of promoting epidermal turnover, promoting keratinocyte differentiation, and promoting tight junction formation.